EP0154842A2 - Medicament containing quaternary 3,4-dihydroisoquinoline salts - Google Patents

Abstract

The present invention relates to new pharmaceuticals with antithrombotic effects, containing a compound of the above general formula <IMAGE> in R1 and R2, which may be the same or different, hydrogen atoms, alkyl or alkoxy groups, R3 an aralkyl group, the phenyl nucleus of which by halogen atoms, alkyl - Or alkoxy groups can be mono-, di- or tri-substituted, where the substituents of the phenyl nucleus can be the same or different, and X is the anion of a physiologically tolerated inorganic or organic acid, their use and preparation.

Description

Quaternary 3,4-dihydroisoquinolinium salts have already been described in the literature (see, for example, Chim. Ther. 6, 358-366 and 462-468 (1971), JCS Chem. Comm. 19, 740-741 (1973), Can. J. Chem. 58, 2770-2779 (1980) and J. Org. Chem. 45, 3176-3181 (1980)). These compounds represent intermediate products, among others. for the production of 1,2,3,4-tetrahydro-isoquinolines with valuable pharmacological properties.

in der

• R₁ und R₂, die gleich oder verschieden sein können, Wasserstoffatome, Alkyl- oder Alkoxygruppen mit jeweils 1 bis 3 Kohlenstoffatomen im Alkylteil,
• R₃ eine Aralkylgruppe mit 7 bis 9 Kohlenstoffatomen, deren Phenylkern durch Halogenatome, Alkyl- oder Alkoxygruppen mit jeweils 1 bis 3 Kohlenstoffatomen im Alkylteil mono-, di-oder trisubstituiert sein kann, wobei die Substituenten des Phenylkerns gleich oder verschieden sein können, und
• X das Anion einer physiologisch verträglichen anorganischen oder organischen Säure bedeuten, wertvolle pharmakologische Eigenschaften aufweisen, insbesondere eine antithrombotische Wirkung.

It has now been found that the 3,4-dihydroisoquinolinium salts of the general formula

in the

• R ₁ and R ₂ , which may be the same or different, are hydrogen atoms, alkyl or alkoxy groups each having 1 to 3 carbon atoms in the alkyl part,
• R _{3 is} an aralkyl group with 7 to 9 carbon atoms, the phenyl nucleus of which may be mono-, di- or tri-substituted by halogen atoms, alkyl or alkoxy groups each having 1 to 3 carbon atoms in the alkyl part, the substituents of the phenyl nucleus being able to be identical or different, and
• X is the anion of a physiologically compatible inorganic or organic acid, has valuable pharmacological properties, in particular an antithrombotic effect.

The present invention thus relates to new medicaments with antithrombotic effects, containing a compound of the general formula I above, their use and preparation, and the new compounds.

For the meanings mentioned in the definition of the radicals R ₁ to R ₃ and X at the outset, for example

R ₁ and R ₂ , which may be the same or different, each have the meaning of the hydrogen atom, the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy group,

for R ₃ that of benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenyl-n-propyl, 2-phenyl-n-propyl, 3-phenyl-n-propyl, l-methyl-2 -phenyl-ethyl, fluorobenzyl, chlorobenzyl, bromobenzyl, difluorobenzyl, dichlorobenzyl, dibromobenzyl, methylbenzyl, ethylbenzyl, isopropylbenzyl, dimethylbenzyl, ethyl, methylbenzyl, trimethylbenoxybenzyl, methoxybenzyl, methoxybenzyl Trimethoxybenzyl, ethoxybenzyl, diethoxybenzyl, chloromethylbenzyl, chloromethoxybenzyl, bromochlorobenzyl, bromomethylbenzyl, bromomethoxybenzyl, 2- (chlorophenyl) ethyl, 2- (bromophenyl) -ethyl-, 2- (methylphenyl) -ethyl-, 2- (methoxyphenyl) -ethyl-, 3- (chlorophenyl) -n-propyl-, 3- (bromophenyl) -n-propyl-, 3- (methylphenyl) - n-propyl or 3- (methoxyphenyl) n-propyl group and for X that of the anion of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid or p-toluenesulfonic acid.

Preferred compounds of the above general formula I are those in which R ₁ and R ₂ , which may be the same or different, are hydrogen atoms, methyl or methoxy groups and

R _{3 represents} a benzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, methoxybenzyl or trimethoxybenzyl group,

in particular, however, those compounds in which R ₁ and R ₂ each have a methoxy group, R ₃ a 2-chlorobenzyl, 2-methoxybenzyl or 3,4,5-trimethoxybenzyl group and

X is the anion of a physiologically acceptable acid.

• a.) Umsetzung eines 3,4-Dihydro-isochinolins der allgemeinen Formel
  
  in der
  • R₁ und R₂ wie eingangs definiert sind, mit einer Verbindung der allgemeinen Formel
    
    in der
  • R₃ wie eingangs definiert ist und
  • Y einen nukleophil austauschbaren Rest wie ein Halogenatom oder einen Sulfonsäurerest, z.B. ein Chlor-, Brom- oder Jodatom, eine Methansulfonyloxy- oder p-Toluolsulfonyloxygruppe, bedeuten.

The compounds of the above general formula are obtained, for example, by the following processes:

• a.) Implementation of a 3,4-dihydro-isoquinoline of the general formula
  
  in the
  • R ₁ and R _{2 are} as defined in the introduction, with a compound of the general formula
    
    in the
  • R _{3 is} as defined at the beginning and
  • Y is a nucleophilically exchangeable radical such as a halogen atom or a sulfonic acid radical, for example a chlorine, bromine or iodine atom, a methanesulfonyloxy or p-toluenesulfonyloxy group.

The reaction is advantageously carried out in a solvent or solvent mixture such as diethyl ether, tetrahydrofuran, dioxane, toluene, ethyl acetate, methylene chloride, ethylene chloride, chloroform, ethanol, isopropanol, acetonitrile or tetrahydrofuran / toluene at temperatures between 0 and 150 ° C, but preferably at temperatures between 10 and 60 ° C. However, the reaction can also be carried out without a solvent.

in der R₁ bis R₃ wie eingangs definiert sind, in Gegenwart eines sauren Kondensationsmittels.b.) Cyclization of an N-formyl compound of the general formula optionally formed in the reaction mixture

in which R ₁ to R _{3 are} as defined in the introduction, in the presence of an acidic condensing agent.

The reaction is carried out in the presence of an acidic condensing agent such as polyphosphoric acid, concentrated sulfuric acid or phosphorus oxychloride, optionally in a solvent such as toluene, chlorobenzene, xylene or dichlorobenzene at elevated temperatures, e.g. at temperatures between 50 ° C and the boiling point of the reaction mixture. However, the reaction can also be carried out without a solvent.

If a compound of general formula I in which X represents a different anion than the desired anion is obtained according to process a) or b), this compound can be converted into its base, e.g. be converted into the desired compound by means of an alkali metal hydroxide such as sodium hydroxide solution or potassium hydroxide solution, and subsequent addition with an appropriate acid.

The compounds of general formulas II to IV used as starting materials are known from the literature or can also be obtained by processes known from the literature. Thus there is obtained a _3,4-D ihydro-isoquinoline of the general formula II by cyclisation of a corresponding N-formyl-2-phenylethylamine and a compound of general formula IV by formylation of a entpsrechenden N-aralkyl-2-phenylethylamine.

As already mentioned at the beginning, the compounds of the general formula I have valuable pharmacological properties, namely, in addition to an inhibitory effect on the tendency to aggregate tumor cells, in particular an antithrombotic effect.

• A = 2-(2-Chlorbenzyl)-6,7-dimethoxy-3,4-dihydro-iso- chinolinium-hydrogensulfat,
• B = 2-(2-Chlorbenzyl)-3,4-dihydro-isochinolinium-hydrogensulfat und
• C = 2-(3,4,5-Trimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroiso- chinolinium-chlorid
  auf ihre biologischen Eigenschaften wie folgt untersucht:

For example, the connections

• A = 2- (2-chlorobenzyl) -6,7-dimethoxy-3,4-dihydro-isoquinolinium hydrogen sulfate,
• B = 2- (2-chlorobenzyl) -3,4-dihydro-isoquinolinium hydrogen sulfate and
• C = 2- (3,4,5-trimethoxybenzyl) -6,7-dimethoxy-3,4-dihydroisoquinolinium chloride
  examined for their biological properties as follows:

1.) Antithrombotic effect (see BORN and CROSS, J. Physiol. 170, 397 (1964):

3 male rats per treatment group, each weighing about 500 g. The substances to be examined are suspended in 1% tylose (A and B) or in distilled water. dissolved (C), in a volume of 0.2 ml per 100 g animal weight administered by gavage. Shortly before the blood is drawn (1 hour after substance administration), the animals are anesthetized with pentobarbital sodium (50 mg / kg i.p.). After opening the abdomen, the required amount of blood is removed by aortic puncture.

The blood is anticoagulated with sodium citrate (0.2% final concentration). Since the aggregation before and after substance administration in rats cannot be measured on the same animal, it has proven to be useful to compare animal collectives whose plasmas have been pooled. Multiple determinations can also be carried out in this way.

Platelet aggregation is measured in platelet-rich plasma (PRP) (amount of plasma per experiment: 1 ml). To obtain PRP, the blood is centrifuged for 10 minutes at 1000 to 1200 revolutions per minute (approx. 150 g). The platelet-poor plasma for calibrating the aggregometer is obtained by centrifuging at 4000 rpm for 10 minutes.

The course of the decrease in the optical density of the platelet suspension after the addition of collagen is measured photometrically and recorded. The curve height in mm, which is measured at the time of maximum light transmission, is the measure of the aggregation strength. A 6-channel aggregometer is used for the measurements.

The amount of collagen (collagen from Hormonchemie, 2 to 5 µl / ml plasma) is chosen so that an irreversible reaction curve results.

The substance-treated animal groups are compared with untreated control groups.

2. Acute toxicity:

The compounds A, B and C are well tolerated, since they do not have any toxic side effects at the highest doses (10 mg / kg po).

The orienting acute toxicity of substance B on the mouse was tested after oral administration of a dose of 250 mg / kg in a group of 10 animals. None of the animals died during the observation period of 14 days.

According to the invention, the compounds of general formula I are suitable on the basis of their pharmacological properties for the prophylaxis of thromboembolic disorders such as coronary infarction, cerebral infarction, and so-called. transient ischaemic attacks, amaurosis fugax and for the prophylaxis of arteriosclerosis and metastasis.

For this purpose, these can be used together with one or more inert customary carriers and / or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty acid paraffin stearate, such as hard fatty acid paraffin stearate, such as hard fatty acid paraffin stearate, such as hard fatty acid paraffin stearate, such as hard fat paraffin stearate , Walrat, Sorbitanmonostearat or their suitable mixtures, if necessary in combination with other active substances, work into the usual galenical preparation forms such as dragées, tablets, capsules, suppositories, ampoules, drops or suspensions. The daily dose in adults is expediently 500 to 1000 mg, preferably 600 to 900 mg, divided into 2 to 4 individual doses.

The following examples are intended to explain the invention in more detail:

Example A 6,7-dimethoxy-3,4-dihydro-isoquinoline a.) N-Formyl-2- (3,4-dimethoxyphenyl) ethylamine

181.2 g (1 mol) of 2- (3,4-dimethoxyphenyl) ethylamine and 181.9 g (1.1 mol) of chloral hydrate are mixed and heated to 120 ° C. with stirring. The mixture is heated to 120 ° C. for 20 minutes and volatile constituents (chloroform and water) are removed in a water jet vacuum at an oil bath temperature of 140 ° C. An oil remains, which is processed without further cleaning.

b.) 6,7-Dimethoxy-3,4-dihydroisoquinoline

The N-formyl-2- (3,4-dimethoxyphenyl) ethylamine obtained according to Example a) is stirred with 1 kg of polyphosphoric acid and heated to 140 ° C. (oil bath temperature), the reaction mixture foaming strongly from an internal temperature of 70 ° C. begins. An internal temperature of approx. 140 ° C is reached after 30 minutes. It is then kept at this temperature for a further 30 minutes. The mixture is then poured onto 1 l of water and concentrated with 1.8 l of ice. Ammonia made alkaline. The reaction product is extracted several times with ethyl acetate, the ethyl acetate phase is washed with water, dried over magnesium sulfate and evaporated. Yield: 142.5 g (75% of theory) of oil.

For further cleaning, the base is dissolved in 350 ml of ethanol and concentrated with 40 ml. Sulfuric acid added. After cooling, the precipitated salt is suctioned off, washed with cold ethanol and dried (forced air drying cabinet, 60 ° C.).

Yield: 179.5 g (62% of theory), melting point of the hydrogen sulfate: 185-187 ° C.

• 3,4-Dihydroisochinolin
• Kp_{208 Pa}: 110°C

The following connections are obtained analogously:

• 3,4-dihydroisoquinoline
• Kp _{208 Pa} : 110 ° C

6-methoxy-3,4-dihydroisoquinoline Melting point of the hydrogen sulfate: 166-168 ° C (from ethanol)

5-methyl-3,4-dihydroisoquinoline Melting point of the hydrogen sulfate: 188-190 ° C (from ethanol)

6,7-dimethyl-3,4-dihydroisoquinoline Melting point of the hydrogen sulfate: 183-185 ° C (from ethanol)

Example B 2- (2-chlorobenzyl) -6,7-dimethoxy-3,4-dihydroisoquinolinium hydrogen sulfate

173.7 g (0.6 mol) of 6,7-dimethoxy-3,4-dihydroisoquinoline hydrogen sulfate are dissolved in 300 ml of water and concentrated using. Ammonia is converted into the free base, which is extracted 4 times with ethyl acetate. It is washed with water and the ethyl acetate phase is dried and evaporated in vacuo. The base obtained (108.3 g = 0.57 mol) is dissolved in 300 ml of dry dioxane and 100 g (0.62 mol) of 2-chlorobenzyl chloride are added. After 10 minutes, the 6,7-dimethoxy-3,4-dihydroisoquinolinium chloride begins to precipitate. The mixture is stirred for 4 days at room temperature and 10 ml (12.7 g) of 2-chlorobenzyl chloride are added again on the 3rd day.

After 4 days, the salt is suctioned off, washed with dioxane and ether and dried.

Yield: 177.1 g (84% of theory), melting point of the chloride: 196 ° C. (from ethanol / ethyl acetate) C ₁₈ H ₁₉ C ₁₂ NO ₂ (352.27)

To convert the hydrogen sulfate, the chloride is dissolved in water, made alkaline with 15N sodium hydroxide solution, a thick precipitate being formed. It is extracted with chloroform, washed, dried and evaporated. The residue obtained is dissolved in 450 ml of isopropanol and carefully concentrated with 27.5 ml. Sulfuric acid added. After cooling, the crystalline salt is filtered off, washed with cold isopropanol and ether and dried.

Yield: 138.4 g (66% of theory), melting point: 227-229 ° C (from methanol) C ₁₈ H ₂₀ ClNO ₆ S (413.89)

Example C

2- (2-chlorobenzyl) -3,4-dihydroisoquinolinium hydrogen sulfate

Prepared analogously to Example B from 3,4-dihydroisoquinoline and 2-chlorobenzyl chloride in acetonitrile.

Yield: 75% of theory,

Hydrogen sulfate melting point: 190-192 ° C (from isopropanol).

C ₁₆ H ₁₆ ClNO ₄ S (353.84)

Example D

2- (2-chlorobenzyl) -5-methyl-3,4-dihydroisoquinolinium chloride

Prepared analogously to Example B from 5-methyl-3,4-dihydroiso quinoline and 2-chlorobenzyl chloride in dioxane. Yield: 58% of theory, melting point: 166-168 ° C.

Example E 2- (2-chlorobenzyl) -6,7-dimethyl-3,4-dihydroisoquinolinium chloride

Prepared analogously to Example B from 6,7-dimethyl-3,4-dihydroisoquinoline and 2-chlorobenzyl chloride in dioxane.

Yield: 62% of theory, melting point: 127-129 ° C.

Example F 2- (2-chlorobenzyl) -6-methoxy-3,4-dihydroisoquinolinium chloride

Prepared analogously to Example B from 6-methoxy-3,4-dihydroisoquinoline and 2-chlorobenzyl chloride in ethylene chloride. Yield: 95% of theory,

Melting point: 156-158 ° C (decomp., From dioxane). Example G 2-benzyl-6,7-dimethoxy-3,4-dihydroisoquinolinium chloride

Prepared analogously to Example B from 6,7-dimethoxy-3,4-dihydroisoquinoline and benzyl chloride in dioxane.

Yield: 30% of theory, melting point: 181-183 ° C (dec.)

C ₁₈ H ₂₀ ClNO ₂ (317.82)

Example H 2- (2-fluorobenzyl) -6,7-dimethoxy-3,4-dihydroisoquinolinium chloride

Prepared analogously to Example B from 6,7-dimethoxy-3,4-dihydroisoquinoline and 2-fluorobenzyl chloride in ethylene chloride. Yield: 71% of theory,

Melting point: 196-198 ° C (dec.) C ₁₈ H ₁₉ ClFNO ₂ (335.82)

Example I 2- (2-methylbenzyl) -6,7-dimethoxy-3,4-dihydroisoquinolinium chloride

Prepared analogously to Example B from 6,7-dimethoxy-3,4-dihydroisoquinoline and 2-methyl-benzyl chloride in dioxane. Yield: 60% of theory,

Melting point: 193-195 ° C (decomp., From ethanol ether). C ₁₉ H ₂₂ ClNO ₂ (331.85)

Example J 2- (4-methylbenzyl) -6,7-dimethoxy-3 _r 4-dihydroisoquinolinium chloride

Prepared analogously to Example B from 6,7-dimethoxy-3,4-dihydroisoquinoline and 4-methylbenzyl chloride in ethylene chloride. Yield: 57% of theory,
Melting point: 181-183 ° C (dec.).

Example K 2- (4-chlorobenzyl) -6,7-dimethoxy-3,4-dihydroisoquinolinium- chloride

Prepared analogously to Example B from 6,7-dimethoxy-3,4-dihydroisoquinoline and 4-chlorobenzyl chloride in ethylene chloride. Yield: 85% of theory, melting point: 182-184 ° C (dec.) C ₁₈ H ₁₉ Cl ₂ NO ₂ (352.27)

Example L 2- (3,4,5-trimethoxybenzyl) -6,7-dimethoxy-3,4-dihydro-isoquinolinium chloride

Prepared analogously to Example B from 6,7-dimethoxy-3,4-dihydro isoquinoline and 3,4,5-trimethoxybenzyl chloride in dioxane. Yield: 70% of theory, melting point: 187-189 ° C (dec.) C ₂₁ H ₂₆ ClNO ₅ (407.90)

Example M 2- (2-chlorobenzyl) -6,7-dimethoxy-3,4-dihydroisoquinolinium hydrogen sulfate a) N- (2-Chlorobenzyl) -2- (3,4-dimethoxyphenyl) ethylamine

80.3 g (0.443 mol) of 2- (3,4-dimethoxyphenyl) ethylamine and 62 g (0.443 mol) of o-chlorobenzaldehyde are boiled in a water separator in 500 ml of toluene for one hour. The mixture is evaporated, the oily residue is taken up in 500 ml of methanol and, with vigorous cooling and stirring, a solution of 16.9 g (0.443 mol) of sodium borohydride in 50 ml of water is added. When the addition is complete, the mixture is stirred for one hour at room temperature, concentrated in vacuo and the residue is distilled in vacuo.

Yield: 108.8 g (80.2% of theory), b.p. 1 _{6, 9 Pa:} 188-190 ° C.

b) N-Formyl-N- (2-chlorobenzyl) -2- (3,4-dimethoxyphenyl) ethylamine

88.4 g (0.29 mol) of N- (2-chlorobenzyl) -2- (3,4-dimethoxyphenyl) ethylamine are mixed with 52.5 g (0.34 mol) of chloral hydrate and at 30 ° for 30 minutes C. heated. After cooling, it is mixed with ethyl acetate, washed with water, dried and evaporated.

Yield: 103 g (100% of theory).

c) 2- (2-chlorobenzyl) -6 _t 7-dimethoxy-3,4-dihydroisoquinolinium hydrogen sulfate

12.1 g of N-formyl-N- (2-chlorobenzyl) -2- (3,4-dimethoxyphenyl) ethylamine are dissolved in 50 ml of toluene, mixed with 15.2 g = 9 ml of phosphorus oxychloride and 1.5 hours on Reflux cooked. It is evaporated, the residue is mixed with ice, made alkaline with potassium carbonate and extracted with ethyl acetate. The ethyl acetate extract is evaporated. The residue obtained is dissolved in isopropanol and 2 ml of conc. Sulfuric acid. After cooling, the product is filtered off with suction, washed with isopropanol and ether and dried.

Yield: 8.6 g (62.7% of theory), melting point: 226-228 ° C ₁₈ H ₂₀ ClNO ₆ S (413.89)

example 1

Manufacturing:

The active substance is mixed with milk sugar, cellulose and corn starch and granulated with a 15% solution of polyvinylpyrrolidone in water. The moist mass is passed through a sieve, spread out on trays and dried at 45 ° C. After sieving again, magnesium stearate is mixed in and the mixture is compressed into tablets.

Example 2

Manufacturing:

The ready-to-press mixture is produced analogously to Example 1. Core weight 480 mg stamp: 11 mm curved with a radius of curvature of 10 mm.

The dragee cores are coated in a known manner in a dragee kettle with a layer of sugar.

Drage weight: 560 mg

Example 3

Manufacturing:

The hard fat is melted. The ground active substance is homogeneously dispersed in the melt at 38 ° C. It is cooled to 35 ° C and poured into weakly pre-cooled suppository molds.

Suppository weight: 1.7 g

Claims (10)

1. Medicament containing a 3,4-dihydro-isoquinolinium salt of the general formula in the

R ₁ and R ₂ , which may be the same or different, are hydrogen atoms, alkyl or alkoxy groups each having 1 to 3 carbon atoms in the alkyl part, R _{3 is} an aralkyl group with 7 to 9 carbon atoms, the phenyl nucleus of which may be mono-, di- or tri-substituted by halogen atoms, alkyl or alkoxy groups each having 1 to 3 carbon atoms in the alkyl part, the substituents of the phenyl nucleus being able to be identical or different, and X is the anion of a physiologically compatible inorganic or organic acid, in addition to one or more inert carriers and / or diluents. 2. Medicament according to claim 1, containing a 3,4-dihydro-isoquinolinium salt of the general formula I according to claim 1, in which R ₁ and R ₂ , which may be the same or different, are hydrogen atoms, methyl or methoxy groups, R _{3 is} a benzyl -, Fluorobenzyl, chlorobenzyl, bromobenzyl, methoxybenzyl or trimethoxybenzyl group and X is the anion of a physiologically compatible inorganic or organic acid, in addition to one or more inert carriers and / or diluents. 3. Medicament according to claim 1, containing a 3,4-dihydroisoquinolinium salt of the general formula I according to claim 1, in which R ₁ and R ₂ each represent a methoxy group, R _{3 represents} a 2-chlorobenzyl, 2-methoxybenzyl or 3, 4,5-trimethoxybenzyl group and
X is the anion of a physiologically acceptable acid, in addition to one or more inert carriers and / or diluents. 4. Medicament according to claim 1, containing 2- (2-chlorobenzyl) -6,7-dimethoxy-3,4-dihydro-isoquinolinium hydrogen sulfate in addition to one or more inert carriers and / or diluents. 5. Medicament according to claim 1, containing 2- (2-chlorobenzyl) -3,4-dihydro-isoquinolinium hydrogen sulfate in addition to one or more inert carriers and / or diluents. 6. Medicament according to claim 1, containing 2- (3,4,5-trimethoxybenzyl) -6,7-dimethoxy-3,4-dihydroisoquinolinium hydrochloride in addition to one or more inert carriers and / or diluents. 7. Medicament according to claims 1 to 6 for the prophylaxis of thromboembolic diseases such as coronary infarction, cerebral infarction, so-called. transient ischaemic attacks, amaurosis fugax and for the prophylaxis of arteriosclerosis and metastasis. 8. A method for producing a medicament according to claims 1 to 7, characterized in that a compound according to claims 1 to 6 is incorporated into one or more inert carriers and / or diluents. 9. Use of a compound according to claims 1 to 6 for the prophylaxis of thromboembolic diseases such as coronary infarction, cerebral infarction, so-called. transient ischaemic attacks, amaurosis fugax and for the prophylaxis of arteriosclerosis and metastasis. 10. 3,4-dihydro-isoquinolinium salts of the general formula I according to claim 1, in which R ₁ to R ₃ and X are as defined in claim 1, as active pharmaceutical ingredients.